Objective/Hypothesis: We propose the development of novel chemical cycloadditons to provide a method for the construction of structurally diverse Vinca alkaloids, including vindoline and analogs. Specific Aims: (1) Design and synthesize a model system to explore the utility of transannular inverse electron demand Diels-Alder reactions employing alkenyl silanes as enol ether surrogates. (2) Develop an enantioselective cycloaddition cascade to assemble the core of vindoline. (3) Complete an enantioselective total synthesis of vindoline and analogs, providing an opportunity for the development of novel therapeutic agents. Study design: Inspired by novel cycloaddition chemistry recently developed by Boger, we envision extending this chemistry to alkenyl silanes. Through the use of these under-explored functionalities, we aim to develop an expedient enantioselective synthesis of vindoline. The robust nature of the proposed reaction will also allow for deep-seated structural modifications that provide opportunity for biological evaluation of analogs previously unavailable by isolation or synthesis. Cancer relevance: Though the use of innovative chemical synthesis and inspiration from natural products, we can design significantly modified compounds that may address the developed resistance and overall toxicity profiles of the Vinca alkaloids. Additionally, a practical asymmetric synthesis of vindoline could prove a viable alternative to the currently used isolation process from plant materials. PUBLIC HEALTH RELEVANCE: The Vinca alkaloids have contributed significantly to the fight against aggressive cancer, but to date these efforts have been limited to the natural compounds and simple derivatives thereof. Although nature provides us with compounds possessing impressive and often unique biological activity, these structures were not evolved for the treatment of human disease. Through the use of innovative chemical synthesis and inspiration from nature's beautiful creations, we can design significantly modified compounds that may address developed resistance and overall toxicity profiles.